Simona Spinelli

Differential role of the medial and lateral prefrontal cortices in fear and anxiety.

In the rat, both the medial and lateral prefrontal cortices (PFC; mPFC and lPFC, respectively) have direct connections with limbic structures that are important in the expression of fear and anxiety. The present study investigated the behavioral effects of excitotoxic lesions of either the mPFC or the lPFC on conditioned and unconditioned fear paradigms. In both unconditioned fear paradigms (open field, elevated plus-maze), lesions of the mPFC decreased anxiety. In fear conditioning, lPFC lesions substantially increased freezing throughout the different phases of the experiment, whereas mPFC lesions increased freezing to contextual cues and showed reduced freezing to discrete cues. These results support the functional role of the PFC in mediating or modulating central states of fear and anxiety and suggest a functional dissociation between the lPFC and mPFC in their role in fear and anxiety.

Helplessness: a systematic translational review of theory and evidence for its relevance to understanding and treating depression.

Helplessness is a major concept in depression and a major theme in preclinical and clinical depression research. For example, in rodents and humans, the learned helplessness (LH) effect describes a specific deficit in behaviour to control aversive stimuli that is induced by prior exposure to uncontrollable aversive stimuli. The LH effect is objective and valid in that the cause of the behavioural deficit, namely uncontrollability, is clear; furthermore, the deficit induced is underlain by emotional, motivational and cognitive processes that are relevant to depression psychopathology. As a further example, helplessness, hopelessness, external locus of control and causal attribution are inter-related and major themes in psychological theories (primarily cognitive theories) of depression. Despite this broad interest in helplessness, it can be argued that its potential usefulness as a scientific and clinical concept has so far not been investigated optimally, including with respect to its application in research aimed at development of improved anti-depressant pharmacotherapy. The first aim of this review was to describe and integrate the psychological evidence and the neurobiological evidence for the LH effect in rodents and healthy humans and for helplessness in depressed patients. The second aim was to conduct three systematic reviews, namely of rodent studies of the LH effect, rodent studies of effects of psychopharmacological agents on the LH effect, and human studies of efficacy of pharmacotherapeutic and psychotherapeutic treatment on helplessness in depressed patients. With respect to the first aim, the major findings are: the specificity of the LH effect in otherwise non-manipulated rodents and healthy humans has been under-estimated, and the LH effect is a specific learned aversive uncontrollability (LAU) effect. There is theoretical and empirical support for a model in which a specific LAU effect induced by a life event of major emotional significance can function as an aetiological factor for generalised helplessness which can in turn function as an aetiological and maintenance factor for depression. However, to date such models have focused on cognitive mediating processes whereas it is emotional-motivational-cognitive processes (as proposed for the LAU effect) that need to be invoked and understood. The evidence is for analogous neural processes underlying the LAU effect in rodents and healthy humans and helplessness in depression, with the ventro-medial prefrontal cortex exhibiting aversive uncontrollability-dependent activity. With respect to the second aim, the major findings are: the LAU effect is demonstrated quite consistently using a number of different paradigms in rat but is poorly studied in mouse. The rat LAU effect can be reversed by chronic administration of monoamine reuptake inhibitors. The effects of antidepressants on human helplessness have been scarcely studied to-date. The major conclusion is that the LAU effect and generalised helplessness constitute major neuropsychological concepts of high value to future translational research aimed at increased understanding of depression and development of novel, improved antidepressant treatments.

The effects of ibotenic acid lesions of the medial and lateral prefrontal cortex on latent inhibition, prepulse inhibition and amphetamine-induced hyperlocomotion

Hypofunction of prefrontal cortical regions, such as dorsolateral and orbital regions, has been suggested to contribute to the symptomatology of schizophrenia. In the rat, the medial and the lateral prefrontal cortices are considered as homologs of the primate dorsolateral and orbital prefrontal cortices, respectively. The present study investigated in rats the effects of lesions of the medial and lateral prefrontal cortices on latent inhibition, prepulse inhibition and amphetamine-induced activity. These paradigms are known to be modulated by the mesolimbic dopaminergic system, a system that has been suggested to be involved in the symptomatology of schizophrenia. Latent inhibition and prepulse inhibition are disrupted in schizophrenic patients as well as in rats treated with amphetamine. Amphetamine-induced activity was tested under dim light (low stress) and bright light (high stress) because stressful situations selectively increase mesocortical dopamine activity. Lateral prefrontal cortex lesioned animals did not differ in their behavior from control animals in any of the paradigms used in this study. Medial prefrontal cortex lesions did not affect latent inhibition but increased prepulse inhibition. In the amphetamine-induced activity experiment, prior to drug administration, open field locomotion was reduced under bright illumination for all lesion groups. After amphetamine administration, medial prefrontal cortex lesions attenuated the hyperlocomotor effect of the drug under the dim light condition and potentiated it under the bright light condition. The results indicate that medial and lateral prefrontal cortex can be functionally differentiated by their involvement in the modulation of behavior requiring mesocorticolimbic dopamine activation. The results in amphetamine induced activity suggest that the behavioral outcomes associated with medial prefrontal cortex depend on the background (stress) against which the evaluation is made. The results also support the notion that prepulse inhibition may be a better model than latent inhibition of the symptoms of schizophrenia associated with dysfunctional prefrontal activity.

Enhancing effects of nicotine and impairing effects of scopolamine on distinct aspects of performance in computerized attention and working memory tasks in marmoset monkeys

With the CAmbridge Neuropsychological Test Automated Battery (CANTAB), computerized neuropsychological tasks can be presented on a touch-sensitive computer screen, and this system has been used to assess cognitive processes in neuropsychiatric patients, healthy volunteers, and species of non-human primate, primarily the rhesus macaque and common marmoset. Recently, we reported that the common marmoset, a small-bodied primate, can be trained to a high and stable level of performance on the CANTAB five-choice serial reaction time (5-CSRT) task of attention, and a novel task of working memory, the concurrent delayed match-to-position (CDMP) task. Here, in order to increase understanding of the specific cognitive demands of these tasks and the importance of acetylcholine to their performance, the effects of systemic delivery of the muscarinic receptor antagonist scopolamine and the nicotinic receptor agonist nicotine were studied. In the 5-CSRT task, nicotine enhanced performance in terms of increased sustained attention, whilst scopolamine led to increased omissions despite a high level of orientation to the correct stimulus location. In the CDMP task, scopolamine impaired performance at two stages of the task that differ moderately in terms of memory retention load but both of which are likely to require working memory, including interference-coping, abilities. Nicotine tended to enhance performance at the long-delay stage specifically but only against a background of relatively low baseline performance. These data are consistent with a dissociation of the roles of muscarinic and nicotinic cholinergic receptors in the regulation of both sustained attention and working memory in primates.

Prefrontal Thinning Affects Functional Connectivity and Regional Homogeneity of the Anterior Cingulate Cortex in Depression

Major depressive disorder (MDD) is associated with structural and functional alterations in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC). Enhanced ACC activity at rest (measured using various imaging methodologies) is found in treatment-responsive patients and is hypothesized to bolster treatment response by fostering adaptive rumination. However, whether structural changes influence functional coupling between fronto-cingulate regions and ACC regional homogeneity (ReHo) and whether these functional changes are related to levels of adaptive rumination and treatment response is still unclear. Cortical thickness and ReHo maps were calculated in 21 unmedicated depressed patients and 35 healthy controls. Regions with reduced cortical thickness defined the seeds for the subsequent functional connectivity (FC) analyses. Patients completed the Response Style Questionnaire, which provided a measure of adaptive rumination associated with better response to psychotherapy. Compared with controls, depressed patients showed thinning of the right anterior PFC, increased prefrontal connectivity with the supragenual ACC (suACC), and higher ReHo in the suACC. The suACC clusters of increased ReHo and FC spatially overlapped. In depressed patients, suACC ReHo scores positively correlated with PFC thickness and with FC strength. Moreover, stronger fronto-cingulate connectivity was related to higher levels of adaptive rumination. Greater suACC ReHo and connectivity with the right anterior PFC seem to foster adaptive forms of self-referential processing associated with better response to psychotherapy, whereas prefrontal thinning impairs the ability of depressed patients to engage the suACC during a major depressive episode. Bolstering the function of the suACC may represent a potential target for treatment.

Functional lateralization of the anterior insula during feedback processing

Effective adaptive behavior rests on an appropriate understanding of how much responsibility we have over outcomes in the environment. This attribution of agency to ourselves or to an external event influences our behavioral and affective response to the outcomes. Despite its special importance to understanding human motivation and affect, the neural mechanisms involved in self‐attributed rewards and punishments remain unclear. Previous evidence implicates the anterior insula (AI) in evaluating the consequences of our own actions. However, it is unclear if the AI has a general role in feedback evaluation (positive and negative) or plays a specific role during error processing. Using functional magnetic resonance imaging and a motion prediction task, we investigate neural responses to self‐ and externally attributed monetary gains and losses. We found that attribution effects vary according to the valence of feedback: significant valence × attribution interactions in the right AI, the anterior cingulate cortex (ACC), the midbrain, and the right ventral putamen. Self‐attributed losses were associated with increased activity in the midbrain, the ACC and the right AI, and negative BOLD response in the ventral putamen. However, higher BOLD activity to self‐attributed feedback (losses and gains) was observed in the left AI, the thalamus, and the cerebellar vermis. These results suggest a functional lateralization of the AI. The right AI, together with the midbrain and the ACC, is mainly involved in processing the salience of the outcome, whereas the left is part of a cerebello‐thalamic‐cortical pathway involved in cognitive control processes important for subsequent behavioral adaptations. Hum Brain Mapp 35:4428–4439, 2014.

Effects of repeated adolescent stress and serotonin transporter gene partial knockout in mice on behaviors and brain structures relevant to major depression.

In humans, exposure to stress during development is associated with structural and functional alterations of the prefrontal cortex (PFC), amygdala (AMY), and hippocampus (HC) and their circuits of connectivity, and with an increased risk for developing major depressive disorder particularly in carriers of the short (s) variant of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR). Although changes in these regions are found in carriers of the s allele and/or in depressed patients, evidence for a specific genotype × developmental stress effect on brain structure and function is limited. Here, we investigated the effect of repeated stress exposure during adolescence in mice with partial knockout of the 5-HTT gene (HET) vs. wildtype (WT) on early-adulthood behavioral measures and brain structure [using magnetic resonance imaging (MRI)] relevant to human major depression. Behaviorally, adolescent stress (AS) increased anxiety and decreased activity and did so to a similar degree in HET and WT. In a probabilistic reversal learning task, HET-AS mice achieved fewer reversals than did HET-No-AS mice. 5-HTT genotype and AS were without effect on corticosterone stress response. In terms of structural brain differences, AS reduced the volume of two long-range white matter tracts, the optic tract (OT) and the cerebral peduncle (CP), in WT mice specifically. In a region-of-interest analysis, AS was associated with increased HC volume and HET genotype with a decreased frontal lobe volume. In conclusion, we found that 5-HTT and AS genotype exerted long-term effects on behavior and development of brain regions relevant to human depression.

Altered dynamics of brain connectivity in major depressive disorder at-rest and during task performance

Major depressive disorder (MDD) has been associated with alterations in several functional brain networks. Previous studies investigating brain networks in MDD during the performance of a task have yielded inconsistent results with the function of the brain at rest. In this study, we used functional magnetic resonance imaging at rest and during a goal-directed task to investigate dynamics of functional connectivity in 19 unmedicated patients with MDD and 19 healthy controls across both experimental paradigms. Patients had spatial differences in the default mode network (DMN), in the executive network (EN), and in the dorsal attention network (DAN) compared to controls at rest and during task performance. In patients the amplitude of the low frequency (LFO) oscillations was reduced in the motor and in the DAN networks during both paradigms. There was a diagnosis by paradigm interaction on the LFOs amplitude of the salience network, with increased amplitude change between task and rest in patients relative to controls. Our findings suggest that the function of several networks could be intrinsically affected in MDD and this could be viable phenotype for the investigation on the neurobiological mechanisms of this disorder and its treatment.

Amygdala response to self-critical stimuli and symptom improvement in psychotherapy for depression.

BACKGROUND Cognitive-behavioural therapy is efficacious in the treatment of major depressive disorder but response rates are still far from satisfactory. AIMS To better understand brain responses to individualised emotional stimuli and their association with outcome, to enhance treatment. METHOD Functional magnetic resonance imaging data were collected prior to individual psychotherapy. Differences in brain activity during passive viewing of individualised self-critical material in 23 unmedicated out-patients with depression and 28 healthy controls were assessed. The associations between brain activity, cognitive and emotional change, and outcome were analysed in 21 patients. RESULTS Patients showed enhanced activity in the amygdala and ventral striatum compared with the control group. Non-response to therapy was associated with enhanced activity in the right amygdala compared with those who responded, and activity in this region was negatively associated with outcome. Emotional but not cognitive changes mediated this association. CONCLUSIONS Amygdala hyperactivity may lessen symptom improvement in psychotherapy for depression through attenuating emotional skill acquisition.

Anterior cingulate volume predicts response to psychotherapy and functional connectivity with the inferior parietal cortex in major depressive disorder

In major depressive disorder (MDD), the anterior cingulate cortex (ACC) has been associated with clinical outcome as well as with antidepressant treatment response. Nonetheless, the association between individual differences in ACC structure and function and the response to cognitive behavioral therapy (CBT) is still unexplored. For this aim, twenty-five unmedicated patients with MDD were scanned with structural and resting state functional magnetic resonance imaging before the beginning of CBT treatment. ACC morphometry was correlated with clinical changes following psychotherapy. Furthermore, whole-brain resting state functional connectivity with the ACC was correlated with clinical measures. Greater volume in the left subgenual (subACC), the right pregenual (preACC), and the bilateral supragenual (supACC) predicted depressive symptoms improvement after CBT. Greater subACC volume was related to stronger functional connectivity with the inferior parietal cortex and dorsolateral prefrontal cortex. Stronger subACC-inferior parietal cortex connectivity correlated with greater adaptive rumination. Greater preACC volume was associated with stronger functional connectivity with the inferior parietal cortex and ventrolateral prefrontal cortex. In contrast, greater right supACC volume was related to lower functional connectivity with the inferior parietal cortex. These results suggest that ACC volume and its functional connectivity with the fronto-parietal cortex are associated with CBT response in MDD, and this may be mediated by adaptive forms of rumination. Our findings support the role of the subACC as a potential predictor for CBT response.